Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization

Abstract

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1R MSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.

Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure

“…Differential activity of D1 and D2 MSNs has been demonstrated to be important for the formation (Kai et al, 2015) and expression (Hikida et al, 2010) of psychostimulant behavioral sensitization. Specifically, NMDARs expressed in D1 MSNs are necessary for amphetamine sensitization (Beutler et al, 2011). It remains unclear how differential activity of D1+ and D1− MSNs contribute to ethanol related behaviors.…”

GluN1 deletions in D1- and A2A-expressing cell types reveal distinct modes of behavioral regulation

“…Striatal NMDAR signaling has been implicated in the pathophysiology of drug addiction and other psychiatric diseases with motivational or affective components (Beutler et al, 2011; Cahill et al, 2014; Lim et al, 2012; Pascoli et al, 2014; Schwartz et al, 2014). In this report, we demonstrate separable roles for cell type-specific NMDAR function in the regulation of complex behaviors.…”

“…Although much remains to be learned, NMDAR signaling in NAc D1 MSNs has been demonstrated to be necessary for the development of psychostimulant-conditioned behaviors (Beutler et al, 2011; Cahill et al, 2014; Heusner and Palmiter, 2005). However, these experiments did not assess whether D1-NMDAR signaling underlies reinstatement, a model of relapse to drug seeking.…”

Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic α4βδ GABAAReceptors Modulates the Actions of Psychostimulants

“…Because these MSN subtypes can exert opposing actions on certain psychostimulant-induced behaviors (Hikida et al, 2010;Beutler et al, 2011;Ferguson et al, 2011), tonic inhibition via ␣4␤␦-GABA A Rs might cause quite different effects via these two output pathways. To probe pathway-specific effects of ␣4␤␦-GABA A Rs, we investigated cocaine CPP in mice with the ␣4 subunit ablated specifically from either D1-or D2-expressing neurons.…”